Through the action of its membrane bound type I receptor, TGF-beta elicits a wide range of cellular responses that regulate cell proliferation, differentiation and apoptosis in the context-dependent manner. Many of these signaling responses are mediated by Smad proteins. As such, controlling Smad activity is crucial for proper signaling by TGF-beta and its related factors. We found that TGF-beta induces phosphorylation at three sites in the linker region of Smad3 in addition to the two C-terminal serine residues. These linker sites can also be phosphorylated by MAPK and CDKs in response to growth factor stimulation or oncogenic Ras activation. In addition, Smad3 is also subjected to Smurf2-mediated mono-ubiquitination that inhibits its activity through blocking complex formation with Smad4. We found that phosphorylation of the linker T179 is required for Smad3 to interact with Smurf2 and undergo Smurf2-mediated ubiquitination. Therefore, Smad3 linker phosphorylation decreases Smad complex formation and transcriptional activity. In many types of cancer cells, the Smad3 linker sites are constitutively phosphorylated. We found that changes in the linker phosphorylation of Smad3 contribute to TGF-beta switching from a tumor suppressor to a metastasis promoter. Although Smads are involved in the most actions of the TGF-beta, activated TGF-beta receptors also transduce signals through other intracellular signaling pathways. For the past several years, my group has devoted considerable effort in deciphering the specific mechanism by which TGF-beta receptors activate MAP kinases independent of Smads, and elucidating the biological significance of this Smad-independent TGF-beta signaling. Toward these goals, we found that TRAF6 is specifically required for the Smad-independent activation of JNK and p38. Currently, we are in the midst of expanding this finding to uncover additional mechanisms and pathways that function in TGF-beta signaling. We have taken a targeted proteomics approach to identify additional associated proteins of the TGF-beta type I receptor complex. Through this approach, We uncovered several protein kinases that interact and/or are phosphorylated at the early stages of TGF-beta signaling. Further characterization of the candidate proteins should lead to elucidation of additional mechanisms that may account for Smad-independent TGF-beta signaling responses and advance our understanding of the ability of TGF-beta to induce a plethora of diverse biological responses.